Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Rituximab treatment in pediatric-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Development and preliminary validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions (SCAC).

Children and adolescents with complex chronic conditions, including those with life-threatening or life-limiting conditions, are a heterogeneous population. Many individuals exhibit sleep abnormalities that are measurable by proxy questionnaires. No suitable instrument to assess the wide range of different complex chronic conditions is currently available. The aim of the present study was to develop a screening tool-the Sleep Screening for Children and Adolescents with Complex Chronic Conditions-to effectively obtain sleep behaviour information in this population. Following a mixed-method design, potential items for the Sleep Screening for Children and Adolescents with Complex Chronic Conditions questionnaire were defined through literature research and expert meetings. In a pre-test with N = 60 family and professional caregivers, the items' relevance and comprehensibility as well as the instrument's overall design were assessed. For the main test, N = 315 participants were recruited in three tertiary paediatric hospitals. A principal components analysis detected the questionnaire's scales. Item analysis focused on mean values, range, difficulty and discriminatory power. Convergent validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions was assessed via correlations between scale items. Most patients had neurological or neuromuscular diseases. Four scales ("Falling and staying asleep", "Sleep-associated respiration and arousal", "Daytime sleepiness" and "Sleep-associated movements") emerged. The item analysis showed satisfactory discriminative power. In the preliminary validation, all scales correlated positively with a child's care level and with various sleep circumstances items. Three scales additionally correlated with the number of complex chronic condition diagnoses. This newly developed questionnaire can provide clinicians with first indications of possible sleep problems in a growing paediatric population.

Autoimmune Encephalitis with Autoantibodies to NMDAR1 following Herpes Encephalitis in Children and Adolescents.

Herpes simplex virus (HSV) type 1 is a frequent pathogen causing infectious encephalitis (HSVE). Early treatment with intravenous acyclovir has led to a significant decrease in mortality. However, especially in children, deterioration during or after HSVE may occur without any evidence of HSV reactivation or improvement following repeated antiviral therapy. Here, we report 15 patients (age range 3 months to 15 years) who suffered from autoimmune encephalitis with autoantibodies to NMDAR1 following Herpes encephalitis, presenting with movement abnormalities (young children) or neuropsychiatric symptoms (older children) as major complaints, respectively. The diagnosis was based on positive cerebrospinal fluid (CSF) and/or serum anti-NMDAR-antibodies with two children showing only positive CSF antibody findings. The time lag between first symptoms and diagnosis of autoimmune encephalitis was significantly longer than between first symptoms and diagnosis of HSVE (p <0.01). All patients improved during immunosuppressive treatment, during which plasmapheresis or rituximab treatments were applied in 11 patients, irrespective of their age. Despite immunotherapy, no patients relapsed with HSVE. Early diagnosis and treatment of autoimmune encephalitis after HSVE may be associated with a better outcome so that high clinical awareness and routine testing for anti-NMDAR-antibodies after HSVE seems advisable. If autoimmune encephalitis is suspected, antibody testing should also be performed on CSF if negative in serum.

Complement Activation Is a Prominent Feature of MOGAD.

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse-onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021;90:976-982.

Serum neurofilament light-chain levels in children with monophasic myelin oligodendrocyte glycoprotein-associated disease, multiple sclerosis, and other acquired demyelinating syndrome.

OBJECTIVE: To assess the diagnostic and prognostic potential of serum neurofilament light chain (sNfL) in children with first acquired demyelinating syndrome (ADS). METHODS: We selected 129 children with first ADS including 19 children with myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease (MOGAD), 36 MOG/AQP4-seronegative ADS, and 74 with multiple sclerosis (MS) from the BIOMARKER study cohort. All children had a complete set of clinical, radiological, laboratory data and serum for NfL measurement using a highly sensitive digital ELISA (SIMOA). A control group of 35 children with non-inflammatory neurological diseases was included. sNfL levels were compared across patient groups according to clinical, laboratory, neuroradiological features and outcome after 2 years. RESULTS: sNfL levels were significantly increased in MOGAD, seronegative ADS and MS compared to controls (p-value < 0.001), in particular in children with an acute disseminated encephalomyelitis (ADEM)-like magnetic resonance imaging (MRI) pattern (p < 0.001) or longitudinally extensive myelitis (p < 0.01). In pediatric MS, elevated sNfL levels were significantly associated with higher numbers of cerebral (p < 0.001) and presence of spinal (p < 0.05) MRI lesions at baseline and predicted a higher number of relapses (p < 0.05). CONCLUSION: sNfL levels are significantly elevated in all three studied pediatric ADS subtypes indicating neuroaxonal injury. In pediatric MS high levels of sNfL are associated with risk factors for disease progression.

[Practice-relevant autoimmune diseases of the central nervous system in pediatrics: early diagnosis and adequate initiation of treatment]. / Praxisrelevante autoimmune Erkrankungen des zentralen Nervensystems in der Pädiatrie: frühe Diagnose und adäquater Therapiebeginn.

BACKGROUND: Pediatric autoimmune diseases affecting the central nervous system have recently come into the the focus of attention. Important advances have been made in the field of children with multiple sclerosis (MS), which led to a better understanding of the clinical characteristics and treatment options. Furthermore, new autoantibodies against target antigens of neurons, peripheral nerves and the myelin sheath have been detected. OBJECTIVE: This article summarizes new advances in children with MS and addresses the differences to their adult counterparts. In addition, the most important forms of autoimmune encephalitis, such as N­methyl D­aspartate receptor (NMDA-R) or myelin oligodendrocyte glycoprotein (MOG) encephalitis in children are described together with the diagnostic algorithm and therapeutic approach in the event of a suspected autoimmune encephalitis. Lastly, the clinical spectrum of MOG antibody-associated diseases (MOGAD) is detailed.

Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis.

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 µg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. METHODS: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. RESULTS: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. INTERPRETATION: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIGMS study.

BACKGROUND: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. OBJECTIVE: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon ß-1a (30 µg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. METHODS: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIGMS study (N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. RESULTS: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC <0.2 × 109/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. CONCLUSION: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: Practical considerations.

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 1: Results from 163 lumbar punctures in 100 adult patients.

BACKGROUND: New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). OBJECTIVE: To describe systematically the CSF profile in MOG-EM. MATERIAL AND METHODS: Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. RESULTS: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/µl; mostly lymphocytes and monocytes; > 100/µl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood-CSF barrier dysfunction was present also during remission in a substantial number of patients. CONCLUSION: MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients.

BACKGROUND: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). OBJECTIVE: To describe systematically the CSF profile in children with MOG-EM. MATERIAL AND METHODS: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. RESULTS: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/µl; range 6-256; mostly lymphocytes and monocytes; > 100/µl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age. CONCLUSION: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study.

OBJECTIVE: PARADIGMS demonstrated superior efficacy and comparable safety of fingolimod versus interferon ß-1a (IFN ß-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study. METHODS: Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN ß-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA). RESULTS: Of the randomised patients, 107 each were treated with fingolimod and IFN ß-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN ß-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN ß-1a, the latter partially due to accelerated atrophy in the IFN ß-1a group. CONCLUSION: Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN ß-1a in PoMS.

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

Therapy of highly active pediatric multiple sclerosis.

OBJECTIVE: Study aims were to determine the frequency of highly active disease in pediatric multiple sclerosis (MS), the response to natalizumab (NTZ) and fingolimod (FTY) treatment, and the impact of current treatment modalities on the clinical course. METHODS: Retrospective single-center study in the German Center for MS in Childhood and Adolescence. RESULTS: Of 144 patients with first MS manifestation between 2011 and 2015, 41.6% fulfilled the criteria for highly active MS. In total, 55 patients treated with NTZ and 23 with FTY demonstrated a significant reduction in relapse rate (NTZ: 95.2%, FTY: 75%), new T2 lesions (NTZ: 97%, FTY: 81%), and contrast-enhancing lesions (NTZ: 97%, FTY: 93%). However, seven patients switched from NTZ to FTY experienced an increase in disease activity. Comparing pediatric MS patients treated in 2005 with those treated in 2015 showed a 46% reduction in relapse rate and a 44% reduction in mean Expanded Disability Status Scale (EDSS). CONCLUSION: The rate of highly active disease among pediatric MS patients is high; more than 40% in our cohort. Response to NTZ and FTY treatment is similar if not better than observed in adults. Current treatment modalities including earlier treatment initiation and the introduction of NTZ and FTY have significantly improved the clinical course of pediatric MS.